A position for a postdoc is available in the Kebschull Lab at the Department of Biomedical Engineering at the Johns Hopkins School of Medicine in Baltimore, MD, for a start date after January 2021. We develop and apply cutting edge molecular and neuroanatomical tools to study how primordial circuits expanded in evolution to form the complex brains that exist today. We have a special focus on barcode sequencing-based high-throughput connectomics (BRICseq, MAPseq) and in situ sequencing, which we apply in the cerebellar nuclei and brain-wide in different vertebrates. Recent relevant papers include Kebschull et al. 2020 bioRxiv, Huang et al. 2020 Cell, Han et al. 2018 Nature, Kebschull et al. 2016 Neuron.
Candidates must hold a PhD degree (or equivalent) in neuroscience, biomedical engineering, molecular biology, or a related field. The ideal candidate should also have some bioinformatics skills and be passionate about brain mapping and evolution. We particularly encourage applications from any underrepresented or minority group.
Our lab is located on the School of Medicine Campus of Johns Hopkins University, surrounded by world-class neuroscience and biomedical engineering labs. We are committed to establishing a first-class, stimulating, and equitable environment in our new lab to allow you to flourish, achieve your goals, and further your career.
Qualified applicants should send a letter describing their current and future research interests, their CV, and names and contact details for three references to kebschull@jhu.edu. More information is available on https://www.kebschull-lab.org/.
Jaw joints, in most vertebrate animals that have them, form between a bone in the head called the quadrate and one in the mandible called the articular. The mandibles (lower jaw bone) of most vertebrates is compound, made up of fused bones, but we mammals are different. We have lots of different types of teeth that processes our food down by chewing. To help with this we evolved a novel jaw joint that allows for both lateral and front-to-back movements of the jaw against the head.
This new joint is between two bones that are nowhere near each other in non-mammals: the squamosal in the skull and the dentary in the mandible. In some mammals, such as humans, the squamosal is fused with other elements, making the temporal bone. In these species the jaw joint is also called the temporomandibular joint, or TMJ. Remember all those different fused bones in the mandible? Well we modern mammals only have the dentary left. As such, the dentary does many more jobs in mammals than it does in non mammals. In non-mammals the dentary hold the teeth, while in mammals it additionally makes the jaw joint, and accts as the muscle attachment site for the muscles of the jaw.
So where have all the other bones gone? Some appear to have been lost, but other have been repurposed and are now part of hearing apparatus. Remember the quadrate and articular that make the jaw joint in most jawed vertebrate? We mammals still have those bones, but we call them the malleus and incus. Alongside the stapes these bones form the middle ear, are the smallest bones in the body, and transmit sound from the air and through to the sensory cells in the inner ear.
How do we know that parts of the mammal middle ear are homologous to the jaw joint of non-mammals? Well, first fossils: this transition is a classic transitional series. 250 million years ago there were stem-mammals that had double jaw joint, and who’s primary jaw joint became involved in hearing (Morganucodon is a textbook example). But we are not palaeontologists, and so we look to another source of evidence: developmental biology. We know that the middle ear bones of mammals develop as part of the mandible, and only separate after the secondary jaw joint forms (Anthwal et al 2017, Urban et al 2017). However when the jaw joint forms differs across the major groups of mammals.
Schematic comparison of thhe jaw and ear in a non-mammal gecko, stem-mammal fossil Morganucodon, and mammal opossum. From https://elifesciences.org/articles/57860
Comparing living mammal groups
There are three living groups of mammals, which can be sorted into two subclasses. The therian mammals are marsupials (such as kangaroos, wombats and opossums) and eutherians (aka placentals, though marsupials also have placentas), while the monotremes occupy the other subclass. Living monotremes are the five species of echidnas and one species of platypus. They are now found only in Australia and New Guinea. Monotremes retain a number of more basal characters, which include reproduction via egg laying, a sprawling gait, and a cloaca (a single opening for the reproductive defecatory and urinary systems). They also lack nipples, and instead secrete milk from specialised mammary patches. The young then suck up this milk from the skin on the mother,
Eutherian (placental) mammals have a longer foetal period development than marsupials and egg laying monotremes. So, our jaw joint and middle ear develops either in utero or shortly after birth. In contrast, monotremes and marsupials are born relatively early in development, so early in fact that they haven’t made their mammalian jaw joint yet. So how do they feed? The answer, which we investigate in our new paper recently published in eLife, is via their middle ear bones, which are still part of the mandible at this developmental stage.
Using archived and new samples to take an evo-devo approach
Fossils indicate that the final steps of middle ear evolution happened independently in monotremes compared to eutherians and marsupials, so we thought that monotremes might use their middle ear differently at hatching. The problem then was how to look at monotreme young, since they’re hardly a model organism. We do have access to an established lab model marsupial, the opossum Monodelphis domestica, thanks to collaboration with another of my mentors, Karen Sears at UCLA, but monotremes are harder to study. Of the extant monotremes, only the short beaked echidna is not CITES protected, and even that species isn’t amenable to lab work.
Ideally we wanted to look at both extant groups of living monotremes, platypus and echidna. To do so we made use of work done in the past. DMS Watson and others had studied platypus and echidna young in the early 20th century and investigated their cranial development by making histological sections. These slides still exist as part of the Hill Embryology Collection at the Museum für Naturkunde in Berlin, and in the collection of the Zoological Museum in Cambridge. So my PI at King’s College London Abbie Tucker went to Berlin to look at and image the slides there, and we both took turns visiting Cambridge.
Histological sections showing platypus middle ears, from the Cambridge and Berlin museums. These sections were first described by Watson in 1915 (10 day and 80 day) or Green in 1937.
We compared these samples from early last century with lab derived developing mice and new born opossums. Anatomically, you can see big differences between each group, including between the marsupials and monotremes. Monotremes have a tiny incus compared to the malleus. In the youngest animals from the museums we were surprised to see the incus fused to the petrosal in the head. Later on they become separated, but they remain articulated, and these articular surfaces remain cartilaginous when the rest of the bone has ossified.
The opossum and eutherian mammals however have a large incus. In opossums the incus appears to be held in place against the head, or possibly cushioned, by a special mesenchyme rich in extra cellular versican. This mesenchyme is missing from eutherians. We think this mesenchyme allows marsupials to suckle before the jaw joint forms, and that this is a different strategy to the fusion seen in monotremes.
Exploring monotremes futher
The mandibular fusion in monotremes was pretty interesting, as the incus and petrosal developed from distinct parts of the embryo. Mouse and chick studies show that the incus/quadrate forms from first pharyngeal arch neural crest derived ectomesenchyme, whereas the petrosal is mostly mesoderm with a small component of second pharyngeal arch neural crest. So we wanted to look at the monotremes in more detail. What is the developmental anatomy of this fusion? How does the separation occur? To get at these questions we were lucky to collaborate with Marilyn Renfree and Jane Fenelon at the University of Melbourne, and Steve Johnston at the University of Queensland in Australia to look at echidnas at the youngest stages. Marilyn and her team have had access tot a breeding colony of echidnas at the Currumbin WIldlife Sanctuary in Queensland. Look out for their exciting work on in egg and early hatching echidnas.
With these fresh samples we were able to look at protein expression by immunohistochemistry in developing post-hatching monotremes for the first time.
Alcian blue staining (left) and immunohistochemistry in Echidna middle ear at day 0. The cartilages of the middle ear of newly hatched monotremes is fused to the skull between the incus and the petrosal.
We found that the early fusion visible in histology was confirmed by expression of SOX9, a transcription factor that drives cartilage development. In older samples, we also found nuclear beta catenin in the region that would separate the incus and petrosal. Mouse studies show that nuclear beta catenin down regulates cartilage during joint formation. When considered alongside and the cartilaginous articular surfaces we see in the older juvenile specimens we studied form the museums, this nuclear beta catenin expression suggests that a joint forms between the incus and petrosal that may be functional in the feeding process.
Next we looked for any evidence of fusion in mice, taking advantage of genetic reporter lines unavailable in monotremes and marsupials. In simple histology staining, we never see fusion of the incus and petrosal. However, to our surprise, Sox9 Cre reporter mice show that the precursors cells of these two elements are in fact “fused”. So it seems that in mice the fusion between the incus and petrosal is early and transient. We also found expression of a joint marker – Gdf5- between the incus and petrosal in mouse embryos. We then took advantage of Mesp1Cre reporter mice, which labels mesoderm tissue, to test where the fusion in Sox9 expression cells occurred. This line told us that the fusions, at least in mice, occurred between the first arch neural crest of the incus and the second arch crest part of the petrosal.
So what does this all mean?
First, we found that marsupials and monotremes have different anatomical strategies for feeding when they are first born – fusion in monotremes versus bracing or cushioning in marsupials. Second, despite the fact that they never need to have a functioning non-mammal jaw joint, mice have a similar transient articulation between their incus and skull to monotremes. This is despite the independent acquisition of the definitive middle ear form in these groups. Given that both mice and echidnas have an articulation, it seems parsimonious that the common ancestor of therian and monotreme mammals (whose middle ear was still attached to their mandible) would have had an incus petrosal joint. We can therefore speculate that this was early in their life before the secondary jaw joint had fully grown.
In adult mammals the middle ear is connected to the mandible ligaments. Developmental defects in the ear and jaw are closely associated. Jaw trauma can lead to knock-on effected in the middle ear. By studying the evolution and development of the jaw and ear, we can also get a better understanding of these connections.
Position Summary:
The MBL is seeking a candidate for the position of Postdoctoral Scientist in the laboratory of Dr. Blair Paul to investigate physical interactions among uncultivated microbial symbioses from aquatic environments. For more information about our lab’s work, see https://www.mbl.edu/jbpc/staff/bgpaul/. This project is funded by The Betty and Gordon Moore Foundation’s Symbiosis in Aquatic Systems Initiative and offers opportunities to collaborate with the labs of co-investigators at UC Berkeley, UC San Diego, and UC Santa Barbara. The ideal candidate will apply existing skills in biochemistry and genetics to assist with development of a high-throughput workflow for cell isolation. This research will involve a synergistic combination of experimental biology and bioinformatics to examine the molecular interface between microbial symbionts and their hosts. We enthusiastically encourage individuals from backgrounds that are underrepresented in STEM fields to apply for this opportunity.
Additional information: The position is for two years with potential for extension, contingent on performance and funding. Salary will be commensurate with experience and qualifications. For more information about MBL and living on Cape Cod, please visit: https://www.mbl.edu/hr/employment/our-community/.
Basic qualifications: A Ph.D. in biology, microbiology, molecular biology, biochemistry, or a related field is required.
Preferred qualifications: Experience in the following areas is desirable: protein biochemistry, microbial cultivation, and/or bacterial or archaeal genetics.
Instructions: Please apply on the MBL website and provide the following required documents: (1) a cover letter describing your interests, skills, and prior research experience, including any specific experience with the job responsibilities listed above; (2) a curriculum vitae/resume; and (3) the names and contact numbers of three persons who can be contacted for letters of reference, at least one of whom must have acted as your supervisor in a previous research position.
#Biotechnology #Imaging #Arthritis research # Drug discovery # Vienna # Machine learning #Cell differentiation assay #Organ-on-a-chip #Biotechnology #Microfluidic #EVOS7000 #personalized medicine #Automation #Liquid Handling #cell biology #Molecularbiology
Pregenerate is a young startup based on the lively Vienna Biocenter Campus surrounded by 12 other start up companies. At Pregenerate we are revolutionizing arthritis treatment with our organ-on-a-chip platform. This technology will ultimately allow us to stratify patients into targeted treatment subgroups, and even to tell each clinical patient what the best treatment is for their specific arthritis needs directly. Our device is also poised to save pharmaceutical companies billions of dollars and improve the success rates of their drugs to market, partly because we can use human cells to replace animal testing in pharmaceutical research for arthritis treatments.
Rosser, J. et al. Microfluidic nutrient gradient-based three-dimensional chondrocyte culture-on-a-chip as an in vitro equine arthritis model. Mater Today Bio4, 100023, doi:10.1016/j.mtbio.2019.100023 (2019).
Vinatier, C. & Guicheux, J. Cartilage tissue engineering: From biomaterials and stem cells to osteoarthritis treatments. Ann Phys Rehabil Med59, 139-144, doi:10.1016/j.rehab.2016.03.002 (2016).
Haltmayer, E. et al. Co-culture of osteochondral explants and synovial membrane as in vitro model for osteoarthritis. PLoS One14, e0214709, doi:10.1371/journal.pone.0214709 (2019).
Please send the application with CV, academic record and coverletter to faheem@pregenerate.net
Molecular Biologist – technician
Establishment of Gene expression analysis at Pregenerate. Your aim will be to establish robust pipeline for analyzing responses to various medications to indicate the best treatment for arthritis on an individual patient level. Future work will include automating the system using a liquid handler.
Your talents and abilities:
M. Sc. in Life Sciences
Strong expertise in molecular biology (RNA extraction, qPCRs, Immunohistochemistry,…)
Tissue Culture experience
Skills in Excel and R programming would be advantageous
Good organizational skills
Enthusiasm for personalized medicine
Preferred starting date is 1st September, 2020
Imaging specialist
Leading the development of image analysis section at Pregenerate using Organ-on a chip technology. Your aim will be to establish and automated image analysis system to visualize the response of various medication in a 3D microfluidic system.
Your talents and abilities:
PhD in Life Sciences (M Sc. considered)
Strong expertise in imaging and imaging analysis
Image J programming a significant advantage
Experience with Confocal imaging and EVOS 7000
Image automation experience
Experience with microfluidics would advantageous
Skills in Excel and R programming would be advantageous
Project management
Enthusiasm for personalized medicine
Preferred starting time is September / October 2020
Welcome to our monthly trawl for developmental biology (and related) preprints.
This month features a host of preprints on human development at the single cell level (perhaps all submitted in time for Development’s September meeting?), plus insights into how butterflies make clear wings and how worms achieve meiosis, and a whole lot more. Preprints hosted on bioRxiv and arXiv – use these links to get to the section you want.
Astrocyte-neuron crosstalk through Hedgehog signaling mediates cortical circuit assembly
Yajun Xie, Aaron T. Kuan, Wengang Wang, Zachary T. Herbert, Olivia Mosto, Olubusola Olukoya, Manal Adam, Steve Vu, Minsu Kim, Nicolás Gómez, Diana Tran, Claire Charpentier, Ingie Sorour, Michael Y. Tolstorukov, Bernardo L. Sabatini, Wei-Chung Allen Lee, Corey C. Harwell
Spatial and single-cell transcriptional landscape of human cerebellar development
Kimberly A. Aldinger, Zach Thomson, Parthiv Haldipur, Mei Deng, Andrew E. Timms, Matthew Hirano, Gabriel Santpere, Charles Roco, Alexander B. Rosenberg, Belen Lorente-Galdos, Forrest O. Gulden, Diana O’Day, Lynne M. Overman, Steven N. Lisgo, Paula Alexandre, Nenad Sestan, Dan Doherty, William B. Dobyns, Georg Seelig, Ian A. Glass, Kathleen J. Millen
Unravelling the developmental roadmap towards human brown adipose tissue
Stefania Carobbio, Anne-Claire Guenantin, Myriam Bahri, Isabella Samuelson, Floris Honig, Sonia Rodriguez-Fdez, Kathleen Long, Ioannis Kamzolas, Sherine Awad, Dunja Lukovic, Slaven Erceg, Andrew Bassett, Sasha Mendjan, Ludovic Vallier, Barry S. Rosen, Davide Chiarugi, Antonio Vidal-Puig
Primate heart regeneration via migration and fibroblast repulsion by human heart progenitors
Christine Schneider, Kylie S. Foo, Maria Teresa De Angelis, Gianluca Santamaria, Franziska Reiter, Tatjana Dorn, Andrea Bähr, Yat Long Tsoi, Petra Hoppmann, Ilaria My, Anna Meier, Victoria Jurisch, Nadja Hornaschewitz, Sascha Schwarz, Kun Lu, Roland Tomasi, Stefanie Sudhop, Elvira Parrotta, Marco Gaspari, Giovanni Cuda, Nikolai Klymiuk, Andreas Dendorfer, Markus Krane, Christian Kupatt, Daniel Sinnecker, Alessandra Moretti, Kenneth R. Chien, Karl-Ludwig Laugwitz
Neutrophil extracellular traps impair regeneration
Eric Wier, Mayumi Asada, Gaofeng Wang, Martin P. Alphonse, Ang Li, Chase Hintelmann, Christine Youn, Brittany Pielstick, Roger Ortines, Lloyd S. Miller, Nathan K. Archer, Luis A. Garza
Human embryonic stem cells-derived dopaminergic neurons transplanted in parkinsonian monkeys recover dopamine levels and motor behavior
Adolfo López-Ornelas, Itzel Escobedo-Avila, Gabriel Ramírez-García, Rolando Lara-Rodarte, César Meléndez-Ramírez, Beetsi Urrieta-Chávez, Tonatiuh Barrios-García, Verónica A. Cáceres-Chávez, Xóchitl Flores-Ponce, Francia Carmona, Carlos Alberto Reynoso, Carlos Aguilar, Nora E. Kerik, Luisa Rocha, Leticia Verdugo-Díaz, Víctor Treviño, José Bargas, Verónica Ramos-Mejía, Juan Fernández-Ruiz, Aurelio Campos-Romo, Iván Velasco
The developmental and genetic architecture of the sexually selected male ornament of swordtails
Manfred Schartl, Susanne Kneitz, Jenny Ormanns, Cornelia Schmidt, Jennifer L Anderson, Angel Amores, Julian Catchen, Catherine Wilson, Dietmar Geiger, Kang Du, Mateo Garcia-Olazábal, Sudha Sudaram, Christoph Winkler, Rainer Hedrich, Wesley C Warren, Ronald Walter, Axel Meyer, John H Postlethwait
Balancing selection maintains ancient genetic diversity in C. elegans
Daehan Lee, Stefan Zdraljevic, Lewis Stevens, Ye Wang, Robyn E. Tanny, Timothy A. Crombie, Daniel E. Cook, Amy K. Webster, Rojin Chirakar, L. Ryan Baugh, Mark G. Sterken, Christian Braendle, Marie-Anne Félix, Matthew V. Rockman, Erik C. Andersen
A new species of planarian flatworm from Mexico: Girardia guanajuatiensis
Elizabeth M. Duncan, Stephanie H. Nowotarski, Carlos Guerrero-Hernández, Eric J. Ross, Julia A. D’Orazio, Clubes de Ciencia México Workshop for Developmental Biology, Sean McKinney, Longhua Guo, Alejandro Sánchez Alvarado
Gender, race and parenthood impact academic productivity during the COVID-19 pandemic: from survey to action
Fernanda Staniscuaski, Livia Kmetzsch, Eugenia Zandonà, Fernanda Reichert, Rossana C. Soletti, Zelia M.C Ludwig, Eliade F. Lima, Adriana Neumann, Ida V.D. Schwartz, Pamela B. Mello-Carpes, Alessandra S.K. Tamajusuku, Fernanda P. Werneck, Felipe K. Ricachenevsky, Camila Infanger, Adriana Seixas, Charley C. Staats, Leticia de Oliveira
Two postdoc positions are available at the Laboratory of the Biochemistry of Cell Signalling, University of São Paulo’s Institute of Chemistry, Brazil.
The main goal of the laboratory is to understand the signaling pathways that lead to pain to guide the development of new non-opioid analgesics. We aim to study signaling pathways involved in the embryonic development of components of the pain system and the signal transduction processes involved in nociceptive pain mediated by Nerve Growth factor (NGF) and the kinase activated by this growth factor, TrkA.
In another subproject we study the role of the kinase PKMzeta in synaptic remodeling in chronic pain.
Requirements
The applicant should have obtained a PhD degree for less than seven years and be well acquainted with molecular and cell biology. As one of the projects focuses on Developmental Biology, previous experience in this field is desirable but not strictly necessary.
1) Academic curriculum, including contact information for 2-3 references;
2) Cover letter stating your aims and motivation for applying for the position.
Application deadline August 30, 2020.
This opportunity is open to candidates of any nationalities. The selected candidate will receive a FAPESP’s Post-Doctoral fellowship in the amount of R$ 7,373.10 monthly and a research contingency fund, equivalent to 15% of the annual value of the fellowship which should be spent in items directly related to the research activity.
A postdoctoral research position is available in the laboratory of Dr. Kristin Gribble at the Marine Biological Laboratory, Woods Hole, MA. The interests of the lab include the mechanisms and evolution of the biology of aging, and maternal and transgenerational effects on offspring health. We use rotifers as a model system for our work. For more information about our lab’s work and a list of publications, see mbl.edu/jbpc/gribble.
Qualified applicants will have the opportunity to study the genetic and epigenetic mechanisms of aging in a novel experimental model system, focusing on how maternal effects influence offspring health and lifespan. This NSF-CAREER funded research program will use experimental, genetic, biochemical, and bioinformatic approaches to elucidate the mechanisms of transgenerational epigenetic inheritance.
Applicants should posses a Ph.D. in molecular biology, cell biology, biochemistry, genetics, bioinformatics, or a related field. The ideal candidate will have a record of scientific rigor, productivity, and creativity; the ability to work independently and as part of a team; and a strong publication record. Excellent oral and written communication skills are required. Highly motivated individuals with experience in other model systems and a background in biochemistry, cell/molecular biology, epigenetics, and/or bioinformatics are encouraged to apply. Salary will be commensurate with experience and qualifications.
Applicants must apply for this position via the Marine Biological Laboratory careers website. Please submit: a cover letter with a brief description of your research experience and how your expertise will contribute to research on the mechanisms of parental effects and transgenerational inheritance; a CV including a list of publications, and contact information for three references.
The new Center for Stem Cell & Organoid Medicine (CuSTOM) at Cincinnati Children’s Hospital Medical Center (CCHMC) is launching a major new initiative to recruit outstanding tenure-track or tenured faculty at the Assistant to Associate Professor level.
CuSTOM (www.cincinnatichildrens.org/custom) is a multi-disciplinary center of excellence integrating developmental and stem cell biologists, clinicians, bioengineers and entrepreneurs with the common goal of accelerating discovery and facilitating bench-to-bedside translation of organoid technology and regenerative medicine. Faculty in CuSTOM benefit from the unique environment and resources to studies of human development, disease and regenerative medicine using pluripotent stem cell and organoid platforms.
CCHMC is a leader in organoid biology and one of the top ranked pediatric research centers in the world, providing a unique environment for basic and translational research. Among pediatric institutions CCHMC is the third-highest ranking recipient of research grants from the National Institutes of Health. CCHMC continues to make major investments in research supporting discovery with 1.4 million square feet of research space and subsidized state-of-the-art core facilities including a human pluripotent stem cell facility, CRISPR genome editing, high-throughput DNA analysis, biomedical informatics, a Nikon Center of Excellence imaging core and much more.
We invite applications from innovative and collaborative investigators focused on basic or translational research in human development and/or disease using stem cells or organoid models. Successful candidates must hold the PhD, MD, or MD/PhD degrees, and will have a vibrant research program with an outstanding publication record.
Applicants should submit their curriculum vitae, two to three page research statement focused on future plans, and contact information for three people who will provide letters of recommendation to CuSTOM@cchmc.org. Applications must be submitted by December 1st, 2020
The Cincinnati Children’s Hospital Medical Center, and the University of Cincinnati are Affirmative Action/Equal Opportunity Employers, fostering diversity and inclusion. Qualified women and minority candidates are especially encouraged to apply.
In the latest episode of Genetics Unzipped, Kat Arney looks at the ancient war between our genes and the pathogens that infect us, going back thousands of years to the Black Death and before, through to our very latest foe: the SARS-CoV-2 coronavirus behind COVID-19.
With Claire Steves (King’s College London), Christiana Scheib (University of Tartu) and Lucy van Dorp (UCL).
If you enjoy the show, please do rate and review on Apple podcasts and help to spread the word on social media. And you can always send feedback and suggestions for future episodes and guests to podcast@geneticsunzipped.com Follow us on Twitter – @geneticsunzip
The neocortex is the seat of our higher cognitive abilities that distinguish us from other mammals and that make us human (Rakic, 2009). One basis for this crucial feature is the increase in the size of the neocortex during hominin evolution, culminating in modern humans (Striedter, 2005, Azevedo et al., 2009, Kaas, 2013, Sousa et al., 2017, Molnar et al., 2019). A key issue in this context is the identification of genomic determinants that underlie the increased growth of the neocortex during brain development. Once candidate genes have been identified, the challenge then is to demonstrate their role in neocortex expansion in an appropriate system. Here, we summarize the background information that suggested the human-specific gene ARHGAP11B to be a candidate to have contributed to neocortex expansion and folding during human evolution, and explain the rationale for demonstrating this role in an ARHGAP11B-transgenic non-human primate model system, that is, fetuses of the common marmoset. Such functional, developmental and evolutionary studies have so far been rarely performed in transgenic non-human primates. In our recent publication, Heide et al. 2020, we show that the human-specific gene ARHGAP11B, when expressed to physiological levels in the fetal marmoset neocortex, indeed causes neocortex expansion and increases neocortex folding, implying that this gene significantly contributed to human neocortex evolution (Heide et al., 2020). Moreover, we hope that our findings provide evidence in support of the usefulness and feasibility of genetically modified non-human primates for neurodevelopmental and evolutionary studies, as well as other fields of neurobiology.
A need for genetically modifiable non-human primate models in neurobiological studies
Which systems are most appropriate for studying the development of the neocortex with the aim to gain insight into the development and evolution of the human neocortex? Commonly used animal models that lend themselves to genetic modifications have been smooth-brained (lissencephalic) rodents (mouse, rat) and the ferret, a carnivore with a folded (gyrencephalic) brain (Molnar et al., 2006, Sun and Hevner, 2014, Kawasaki, 2018, Zhao and Bhattacharyya, 2018). However, many findings about neocortical development obtained in these model systems cannot be translated as such to humans, as is exemplified, in particular, in the case of many mouse disease models (e.g., mouse models of primary microcephaly (Pinson et al., 2019)).
A recently emerged, promising in vitro model system of human neocortical development that overcomes some of these limitations are human brain organoids (Kadoshima et al., 2013, Lancaster et al., 2013, Camp et al., 2015, Qian et al., 2016, Quadrato et al., 2017). These are 3D cellular assemblies that model the tissue of certain brain regions over a particular developmental time window and recapitulate many aspects of the cytoarchitecture and cell-type complexity of the modelled brain tissue (Heide et al., 2018). Moreover, comparison of brain organoids of human vs. non-human primate origin (macaque, chimpanzee, orang-utan) has led to the identification of human-specific features of neocortical development (Otani et al., 2016, Mora-Bermudez et al., 2016, Pollen et al., 2019, Kanton et al., 2019). Importantly, brain organoids can easily be genetically modified (Fischer et al., 2019), and human brain organoids have been shown to recapitulate gene expression patterns of fetal human neocortex (Camp et al., 2015). However, despite its promise, the brain organoid model system still has certain limitations, such that is does not fully recapitulate the cytoarchitecture, cell-type composition and late and postnatal stages of neocortex development (Heide et al., 2018). Moreover, cell-type specification in brain organoids seems to be impaired due to cellular stress (Bhaduri et al., 2020).
Hence, fetal human brain tissue ex vivo (Rakic, 2006, Florio et al., 2015, Johnson et al., 2015, Pollen et al., 2015, Kalebic et al., 2019, Namba et al., 2020) and non-human primate models (Smart et al., 2002, Rakic, 2006, Kelava et al., 2012, Garcia-Moreno et al., 2012, Betizeau et al., 2013) have been increasingly used to overcome the limitations of the rodent and ferret models and of brain organoids for studying the development of the neocortex with the aim to gain insight into the development and evolution of the human neocortex. However, the use of fetal human brain tissue ex vivo is limited to early stages of neocortical development, and genetic modification approaches can only be conducted – for obvious ethical reasons – with ex vivo fetal human brain tissue. It is for these reasons that genetically modifiable non-human primate models have recently emerged as system of choice to gain insight into human neocortex development and evolution (Sasaki et al., 2009, Niu et al., 2010, Niu et al., 2014, Shi et al., 2019, Heide et al., 2020). A major advantage of non-human primate models is that in terms of morphology, cell-type composition, gene expression and interaction partners, these models are much closer to human neocortex development than the rodent and ferret models. Moreover, genetically modifiable non-human primate models are likely to have huge potential in generating models of neurological and neurodevelopmental disorders.
ARHGAP11B — a human-specific gene that may drive human neocortex expansion and folding?
The ARHGAP11B gene evolved ~5 mya, that is, after the split of the lineage leading to modern humans and the lineage leading to chimpanzee and bonobo, by segmental duplication of the widespread gene ARHGAP11A (Sudmant et al., 2010). In other words, ARHGAP11B is only found in humans and hence is a human-specific gene. However, ARHGAP11B is not a simple copy of ARHGAP11A, as the ARHGAP11B protein corresponds to only the N-terminal one quarter of the ARHGAP11A protein and, importantly, possesses a unique, human-specific 47 amino acid sequence in its C-terminal domain that is key for its function (Florio et al., 2015, Namba et al., 2020). This unique C-terminal protein sequence arises from a single C-to-G nucleotide substitution in ARHGAP11B that generated a novel splice donor site, resulting in the loss of 55 nucleotides upon mRNA splicing. This loss in turn causes a shift in the reading frame, leading to ARHGAP11B’s unique C-terminal 47 amino acid sequence (Florio et al., 2016). Previous functional analyses by strong overexpression of this gene in embryonic mouse (Florio et al., 2015) and ferret (Kalebic et al., 2018) neocortex showed increased numbers of basal progenitor cells and of upper-layer neurons, the class of progenitors and type of cortical neurons, respectively, that have been implicated in neocortex expansion (Lui et al., 2011, Fame et al., 2011, Borrell and Reillo, 2012, Betizeau et al., 2013, Florio and Huttner, 2014, Dehay et al., 2015, Lodato and Arlotta, 2015). Moreover, in the case of mouse, ARHGAP11B overexpression could induce folding of the normally smooth neocortex (Florio et al., 2015). These findings suggested that ARHGAP11B is a candidate gene to have contributed to neocortex expansion and folding during human evolution. However, the key question was whether this gene, when expressed to physiological levels and in a primate model that is evolutionarily closer to human than mouse or ferret, would increase neocortex size and folding.
Which genetically modifiable non-human primate model to choose?
We therefore searched for a genetically modifiable primate model that is evolutionarily as close as (ethically) possible to human and that possesses all relevant stem cell populations at the correct relative abundance in the developing neocortex, to allow us to explore the potential role of ARHGAP11B in the expansion of the neocortex during development and human evolution. This confined our choice to two non-human primate models, the common marmoset (Callithrix jacchus) and the macaque (eitherMacaca mulatta or Macaca fascicularis). We chose to focus on the marmoset, as this New World monkey, while exhibiting many of the features of the large and folded human neocortex, has – in contrast to the macaque – a small and unfolded neocortex, making it thus an ideal model to study ARHGAP11B’s potential contribution to neocortical expansion and folding.
ARHGAP11B increases fetal primate neocortex size and folding
In Heide et al. 2020, we generated, in collaboration with the research groups of Erika Sasaki and Hideyuki Okano in Japan who have pioneered the transgenic marmoset technology (Sasaki et al., 2009), ARHGAP11B-transgenic marmoset fetuses (Figure A) that expressed ARHGAP11B in the developing neocortex under the control of its own, human promoter (Heide et al., 2020).
(A) Cartoon depicting the timeline of the generation of ARHGAP11B-transgenic fetal marmosets. (B) Schematic showing a section through the neocortical wall (left) and brain images (right) of wildtype (WT) and ARHGAP11B-transgenic marmoset fetuses at 101 days of pregnancy; arrowheads, folds; orange dashed line, rostral boundary of wildtype (WT) and ARHGAP11B-transgenic fetal marmoset neocortex; yellow dashed line, caudal boundary of wildtype (WT) fetal marmoset neocortex; red dashed line, caudal boundary of ARHGAP11B-transgenic fetal marmoset neocortex; scale bars, 1 mm.
In the neocortex of these ARHGAP11B-transgenic marmoset fetuses, ARHGAP11B was expressed to physiological levels, that is, to similar levels as in fetal human neocortex, and its expression within the neocortex was confined to neural stem and progenitor cells (Heide et al., 2020). Furthermore, this ARHGAP11B expression increased the abundance of basal radial glia (Heide et al., 2020) – the basal progenitor cell type thought to play a key role in neocortex expansion and folding, notably in human neocortex development (Lui et al., 2011, Borrell and Reillo, 2012 Florio and Huttner, 2014). This was accompanied by an increase in upper-layer neurons (Heide et al., 2020) — the cortical neuron type thought to strongly contribute to our higher cognitive abilities (Fame et al., 2011). At the supracellular level, this ARHGAP11B expression resulted in increased neocortex size and induced folding of the normally unfolded fetal marmoset neocortex (Heide et al., 2020) (Figure B). In summary, our study strongly suggests that ARHGAP11B did contribute to neocortex expansion and folding in the course of human evolution.
Ethical considerations
Experiments involving non-human primates have been under constant public and scientific debate, and it is perfectly legitimate to scrutinize whether or not such experiments are really necessary and to ask whether other animal model systems are available that are appropriate to address the same scientific questions. Furthermore, experiments involving non-human primates should be performed according to the highest ethical standards.
In our case, we reasoned that in order to answer the question whether the human-specific gene ARHGAP11B contributed to neocortex expansion and folding during human evolution, it was necessary to express ARHGAP11B in a suitable non-human primate model, that is, the common marmoset. We limited these experiments and analyses to fetal stages, for two main reasons. First, should ARHGAP11Bexpression increase neocortex size and neuron numbers as we anticipated, the consequences for the postnatal and adult marmosets with regard to behaviour and nervous system performance might be unpredictable. In this context, one should realize that increases in neocortex size and neuron numbers are not necessarily beneficial but can be the underlying cause of certain human diseases (e.g., megalencephaly, polymicrogyria), and accordingly could lead to suffering of the animals (e.g., from seizures). To avoid generating ARHGAP11B-expressing postnatal and adult marmosets, all ARHGAP11B-expressing marmoset fetuses analyzed in our study were newly and individually generated (rather than being descendants of an ARHGAP11B-expressing marmoset line). Second, our previous data had indicated that ARHGAP11B expression increased basal progenitors and upper-layer neurons during the development of the neocortex. This suggested that in our case an analysis of fetal stages of ARHGAP11B-expressing marmosets would be appropriate and constructive, and would allow closely monitoring neocortex development and analyzing it at the relevant stages.
We hope that our study shows that genetically modified non-human primate fetuses can be superior models to understand human neocortex development and evolution. Furthermore, our work will hopefully encourage other researchers from the present and other fields of neurobiology (including disease modelling) to study genetically modified non-human primate models in the future, as (i) such experiments can be performed in an ethically justifiable way (see above), (ii) the results may answer questions that other, non-primate models cannot answer, and (iii) the results most likely can be directly translated to humans.
References
AZEVEDO, F. A. C., CARVALHO, L. R. B., GRINBERG, L. T., FARFEL, J. M., FERRETTI, R. E. L., LEITE, R. E. P., JACOB, W., LENT, R. & HERCULANO-HOUZEL, S. 2009. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J. Comp. Neurol. , 513, 532-541.
BETIZEAU, M., CORTAY, V., PATTI, D., PFISTER, S., GAUTIER, E., BELLEMIN-MÉNARD, A., AFANASSIEFF, M., HUISSOUD, C., DOUGLAS, R. J., KENNEDY, H. & DEHAY, C. 2013. Precursor diversity and complexity of lineage relationships in the outer subventricular zone of the primate. Neuron, 80, 442-457.
BHADURI, A., ANDREWS, M. G., MANCIA LEON, W., JUNG, D., SHIN, D., ALLEN, D., JUNG, D., SCHMUNK, G., HAEUSSLER, M., SALMA, J., POLLEN, A. A., NOWAKOWSKI, T. J. & KRIEGSTEIN, A. R. 2020. Cell stress in cortical organoids impairs molecular subtype specification. Nature, 578, 142-148.
BORRELL, V. & REILLO, I. 2012. Emerging roles of neural stem cells in cerebral cortex development and evolution. Dev Neurobiol, 72, 955-971.
CAMP, J. G., BADSHA, F., FLORIO, M., KANTON, S., GERBER, T., WILSCH-BRÄUNINGER, M., LEWITUS, E., SYKES, A., HEVERS, W., LANCASTER, M., KNOBLICH, J. A., LACHMANN, R., PÄÄBO, S., HUTTNER, W. B. & TREUTLEIN, B. 2015. Human cerebral organoids recapitulate gene expression programs of fetal neocortex development. Proc Natl Acad Sci U S A, 112,15672-7.
DEHAY, C., KENNEDY, H. & KOSIK, K. S. 2015. The outer subventricular zone and primate-specific cortical complexification. Neuron, 85, 683-694.
FAME, R. M., MACDONALD, J. L. & MACKLIS, J. D. 2011. Development, specification, and diversity of callosal projection neurons. Trends Neurosci, 34, 41-50.
FISCHER, J., HEIDE, M. & HUTTNER, W. B. 2019. Genetic modification of brain organoids. Front Cell Neurosci, 13, 558.
FLORIO, M., ALBERT, M., TAVERNA, E., NAMBA, T., BRANDL, H., LEWITUS, E., HAFFNER, C., SYKES, A., WONG, F. K., PETERS, J., GUHR, E., KLEMROTH, S., PRUFER, K., KELSO, J., NAUMANN, R., NÜSSLEIN, I., DAHL, A., LACHMANN, R., PÄÄBO, S. & HUTTNER, W. B. 2015. Human-specific gene ARHGAP11B promotes basal progenitor amplification and neocortex expansion. Science, 347, 1465-1470.
FLORIO, M. & HUTTNER, W. B. 2014. Neural progenitors, neurogenesis and the evolution of the neocortex. Development, 141, 2182-2194.
FLORIO, M., NAMBA, T., PÄÄBO, S., HILLER, M. & HUTTNER, W. B. 2016. A single splice site mutation in human-specific ARHGAP11B causes basal progenitor amplification. Sci Adv, 2,e1601941.
GARCIA-MORENO, F., VASISTHA, N. A., TREVIA, N., BOURNE, J. A. & MOLNAR, Z. 2012. Compartmentalization of cerebral cortical germinal zones in a lissencephalic primate and gyrencephalic rodent. Cereb. Cortex, 22, 482-492.
HEIDE, M., HAFFNER, C., MURAYAMA, A., KUROTAKI, Y., SHINOHARA, H., OKANO, H., SASAKI, E. & HUTTNER, W. B. 2020. Human-specific ARHGAP11B increases size and folding of primate neocortex in the fetal marmoset. Science, eabb2401 [published online ahead of print].
HEIDE, M., HUTTNER, W. B. & MORA-BERMUDEZ, F. 2018. Brain organoids as models to study human neocortex development and evolution. Curr Opin Cell Biol, 55, 8-16.
JOHNSON, M. B., WANG, P. P., ATABAY, K. D., MURPHY, E. A., DOAN, R. N., HECHT, J. L. & WALSH, C. A. 2015. Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nat. Neurosci., 18, 637-646.
KAAS, J. H. 2013. The evolution of brains from early mammals to humans. WIREs Cogn. Sci., 4, 33-45.
KADOSHIMA, T., SAKAGUCHI, H., NAKANO, T., SOEN, M., ANDO, S., EIRAKU, M. & SASAI, Y. 2013. Self-organization of axial polarity, inside-out layer pattern, and species-specific progenitor dynamics in human ES cell-derived neocortex. Proc Natl Acad Sci U S A, 110, 20284-9.
KALEBIC, N., GILARDI, C., ALBERT, M., NAMBA, T., LONG, K. R., KOSTIC, M., LANGEN, B. & HUTTNER, W. B. 2018. Human-specific ARHGAP11B induces hallmarks of neocortical expansion in developing ferret neocortex. eLife, 7, e41241.
KALEBIC, N., GILARDI, C., STEPIEN, B., WILSCH-BRÄUNINGER, M., LONG, K. R., NAMBA, T., FLORIO, M., LANGEN, B., LOMBARDOT, B., SHEVCHENKO, A., KILIMANN, M. W., KAWASAKI, H., WIMBERGER, P. & HUTTNER, W. B. 2019. Neocortical expansion due to increased proliferation of basal progenitors is linked to changes in their morphology. Cell Stem Cell, 24, 535-550 e9.
KANTON, S., BOYLE, M. J., HE, Z. S., SANTEL, M., WEIGERT, A., SANCHIS-CALLEJA, F., GUIJARRO, P., SIDOW, L., FLECK, J. S., HAN, D. D., QIAN, Z. Z., HEIDE, M., HUTTNER, W. B., KHAITOVICH, P., PÄÄBO, S., TREUTLEIN, B. & CAMP, J. G. 2019. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Nature, 574, 418-422.
KAWASAKI, H. 2018. Molecular investigations of the development and diseases of cerebral cortex folding using gyrencephalic mammal ferrets. Biol Pharm Bull, 41, 1324-1329.
KELAVA, I., REILLO, I., MURAYAMA, A. Y., KALINKA, A. T., STENZEL, D., TOMANCAK, P., MATSUZAKI, F., LEBRAND, C., SASAKI, E., SCHWAMBORN, J. C., OKANO, H., HUTTNER, W. B. & BORRELL, V. 2012. Abundant occurrence of basal radial glia in the subventricular zone of embryonic neocortex of a lissencephalic primate, the common marmoset Callithrix jacchus. Cereb. Cortex, 22, 469-481.
LANCASTER, M. A., RENNER, M., MARTIN, C. A., WENZEL, D., BICKNELL, L. S., HURLES, M. E., HOMFRAY, T., PENNINGER, J. M., JACKSON, A. P. & KNOBLICH, J. A. 2013. Cerebral organoids model human brain development and microcephaly. Nature, 501, 373-9.
LODATO, S. & ARLOTTA, P. 2015. Generating neuronal diversity in the mammalian cerebral cortex. Annu. Rev. Cell Dev. Biol., 31, 699-720.
LUI, J. H., HANSEN, D. V. & KRIEGSTEIN, A. R. 2011. Development and evolution of the human neocortex. Cell, 146, 18-36.
MOLNAR, Z., CLOWRY, G. J., SESTAN, N., ALZU’BI, A., BAKKEN, T., HEVNER, R. F., HUPPI, P. S., KOSTOVIC, I., RAKIC, P., ANTON, E. S., EDWARDS, D., GARCEZ, P., HOERDER-SUABEDISSEN, A. & KRIEGSTEIN, A. 2019. New insights into the development of the human cerebral cortex. J Anat, 235, 432-451.
MOLNAR, Z., METIN, C., STOYKOVA, A., TARABYKIN, V., PRICE, D. J., FRANCIS, F., MEYER, G., DEHAY, C. & KENNEDY, H. 2006. Comparative aspects of cerebral cortical development. Eur J Neurosci, 23, 921-34.
MORA-BERMUDEZ, F., BADSHA, F., KANTON, S., CAMP, J. G., VERNOT, B., KOHLER, K., VOIGT, B., OKITA, K., MARICIC, T., HE, Z., LACHMANN, R., PÄÄBO, S., TREUTLEIN, B. & HUTTNER, W. B. 2016. Differences and similarities between human and chimpanzee neural progenitors during cerebral cortex development. eLife, 5, e18683.
NAMBA, T., DOCZI, J., PINSON, A., XING, L., KALEBIC, N., WILSCH-BRÄUNINGER, M., LONG, K. R., VAID, S., LAUER, J., BOGDANOVA, A., BORGONOVO, B., SHEVCHENKO, A., KELLER, P., DRECHSEL, D., KURZCHALIA, T., WIMBERGER, P., CHINOPOULOS, C. & HUTTNER, W. B. 2020. Human-specific ARHGAP11B acts in mitochondria to expand neocortical progenitors by glutaminolysis. Neuron, 105, 867-881 e9.
NIU, Y., YU, Y., BERNAT, A., YANG, S., HE, X., GUO, X., CHEN, D., CHEN, Y., JI, S., SI, W., LV, Y., TAN, T., WEI, Q., WANG, H., SHI, L., GUAN, J., ZHU, X., AFANASSIEFF, M., SAVATIER, P., ZHANG, K., ZHOU, Q. & JI, W. 2010. Transgenic rhesus monkeys produced by gene transfer into early-cleavage-stage embryos using a simian immunodeficiency virus-based vector. Proc Natl Acad Sci U S A, 107, 17663-7.
NIU, Y. Y., SHEN, B., CUI, Y. Q., CHEN, Y. C., WANG, J. Y., WANG, L., KANG, Y., ZHAO, X. Y., SI, W., LI, W., XIANG, A. P., ZHOU, J. K., GUO, X. J., BI, Y., SI, C. Y., HU, B., DONG, G. Y., WANG, H., ZHOU, Z. M., LI, T. Q., TAN, T., PU, X. Q., WANG, F., JI, S. H., ZHOU, Q., HUANG, X. X., JI, W. Z. & SHA, J. H. 2014. Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. Cell, 156, 836-843.
OTANI, T., MARCHETTO, M. C., GAGE, F. H., SIMONS, B. D. & LIVESEY, F. J. 2016. 2D and 3D stem cell models of primate cortical development identify species-specific differences in progenitor behavior contributing to brain size. Cell Stem Cell, 18, 467-80.
PINSON, A., NAMBA, T. & HUTTNER, W. B. 2019. Malformations of human neocortex in development – their progenitor cell basis and experimental model systems. Front Cell Neurosci, 13, 305.
POLLEN, A. A., BHADURI, A., ANDREWS, M. G., NOWAKOWSKI, T. J., MEYERSON, O. S., MOSTAJO-RADJI, M. A., DI LULLO, E., ALVARADO, B., BEDOLLI, M., DOUGHERTY, M. L., FIDDES, I. T., KRONENBERG, Z. N., SHUGA, J., LEYRAT, A. A., WEST, J. A., BERSHTEYN, M., LOWE, C. B., PAVLOVIC, B. J., SALAMA, S. R., HAUSSLER, D., EICHLER, E. E. & KRIEGSTEIN, A. R. 2019. Establishing cerebral organoids as models of human-specific brain evolution. Cell, 176, 743-756.
POLLEN, A. A., NOWAKOWSKI, T. J., CHEN, J., RETALLACK, H., SANDOVAL-ESPINOSA, C., NICHOLAS, C. R., SHUGA, J., LIU, S. J., OLDHAM, M. C., DIAZ, A., LIM, D. A., LEYRAT, A. A., WEST, J. A. & KRIEGSTEIN, A. R. 2015. Molecular identity of human outer radial glia during cortical development. Cell, 163, 55-67.
QIAN, X., NGUYEN, H. N., SONG, M. M., HADIONO, C., OGDEN, S. C., HAMMACK, C., YAO, B., HAMERSKY, G. R., JACOB, F., ZHONG, C., YOON, K. J., JEANG, W., LIN, L., LI, Y., THAKOR, J., BERG, D. A., ZHANG, C., KANG, E., CHICKERING, M., NAUEN, D., HO, C. Y., WEN, Z., CHRISTIAN, K. M., SHI, P. Y., MAHER, B. J., WU, H., JIN, P., TANG, H., SONG, H. & MING, G. L. 2016. Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell,165, 1238-1254.
QUADRATO, G., NGUYEN, T., MACOSKO, E. Z., SHERWOOD, J. L., MIN YANG, S., BERGER, D. R., MARIA, N., SCHOLVIN, J., GOLDMAN, M., KINNEY, J. P., BOYDEN, E. S., LICHTMAN, J. W., WILLIAMS, Z. M., MCCARROLL, S. A. & ARLOTTA, P. 2017. Cell diversity and network dynamics in photosensitive human brain organoids. Nature, 545, 48-53.
RAKIC, P. 2006. A century of progress in corticoneurogenesis: from silver impregnation to genetic engineering. Cereb Cortex, 16 Suppl 1, i3-17.
RAKIC, P. 2009. Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci., 10, 724-735.
SASAKI, E., SUEMIZU, H., SHIMADA, A., HANAZAWA, K., OIWA, R., KAMIOKA, M., TOMIOKA, I., SOTOMARU, Y., HIRAKAWA, R., ETO, T., SHIOZAWA, S., MAEDA, T., ITO, M., ITO, R., KITO, C., YAGIHASHI, C., KAWAI, K., MIYOSHI, H., TANIOKA, Y., TAMAOKI, N., HABU, S., OKANO, H. & NOMURA, T. 2009. Generation of transgenic non-human primates with germline transmission. Nature, 459, 523-7.
SHI, L., LUO, X., JIANG, J., CHEN, Y., LIU, C., HU, T., LI, M., LIN, Q., LI, Y., HUANG, J., WANG, H., NIU, Y., SHI, Y., STYNER, M., WANG, J., LU, Y., SUN, X., YU, H., JI, W. & SU, B. 2019. Transgenic rhesus monkeys carrying the human MCPH1 gene copies show human-like neoteny of brain development. National Science Review, 6, 480-493.
SMART, I. H., DEHAY, C., GIROUD, P., BERLAND, M. & KENNEDY, H. 2002. Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb. Cortex, 12, 37-53.
SOUSA, A. M. M., MEYER, K. A., SANTPERE, G., GULDEN, F. O. & SESTAN, N. 2017. Evolution of the human nervous system function, structure, and development. Cell, 170, 226-247.
STRIEDTER, G. F. 2005. Principles of Brain Evolution, Sinauer Associates Inc.
SUDMANT, P. H., KITZMAN, J. O., ANTONACCI, F., ALKAN, C., MALIG, M., TSALENKO, A., SAMPAS, N., BRUHN, L., SHENDURE, J. & EICHLER, E. E. 2010. Diversity of human copy number variation and multicopy genes. Science, 330, 641-646.
SUN, T. & HEVNER, R. F. 2014. Growth and folding of the mammalian cerebral cortex: from molecules to malformations. Nat. Rev. Neurosci., 15, 217-232.
ZHAO, X. & BHATTACHARYYA, A. 2018. Human models are needed for studying human neurodevelopmental disorders. Am J Hum Genet, 103, 829-857.
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In the latest episode of Genetics Unzipped, Kat Arney looks at the ancient war between our genes and the pathogens that infect us, going back thousands of years to the Black Death and before, through to our very latest foe: the SARS-CoV-2 coronavirus behind COVID-19.